A5007711647- MicroRNA in disease regulation
- PI3K/AKT/mTOR signaling in cancer
- Mitochondrial Function and Pathology
- Circular RNAs in diseases
- Polyamine Metabolism and Applications
- RNA modifications and cancer
- Endoplasmic Reticulum Stress and Disease
- Phosphodiesterase function and regulation
- Adipose Tissue and Metabolism
- Mast cells and histamine
- Redox biology and oxidative stress
- Cancer-related molecular mechanisms research
- CAR-T cell therapy research
- CRISPR and Genetic Engineering
- RNA Research and Splicing
- Autophagy in Disease and Therapy
- Tuberous Sclerosis Complex Research
- Receptor Mechanisms and Signaling
- Nitric Oxide and Endothelin Effects
- Cholinesterase and Neurodegenerative Diseases
- Plant Virus Research Studies
- Cardiac Fibrosis and Remodeling
- Protein Kinase Regulation and GTPase Signaling
- Heart Failure Treatment and Management
- Elasticity and Material Modeling
Johns Hopkins University
2014-2023
Johns Hopkins Medicine
2017-2023
Emory University Hospital
2021
Notre Dame of Maryland University
2014
MicroRNAs (miRNAs) are small non-coding RNAs, which inhibit the stability and/or translation of a mRNA. miRNAs have been found to play powerful role in various cardiovascular diseases. Recently, we demonstrated that microRNA (miR-181c) can be encoded nucleus, processed mature form cytosol, translocated into mitochondria, and ultimately regulate mitochondrial gene expression. However vivo impact miR-181c is unknown. Here report an in-vivo method for administration rats, leads reduced exercise...
Aims: MicroRNAs (miRNAs), one type of noncoding RNA, modulate post-transcriptional gene expression in various pathogenic pathways 2 diabetes (T2D). Currently, little is known about how miRNAs influence disease pathogenesis by targeting cells at a distance. The purpose this study was to investigate the role exosomal during T2D. Results: We show that miR-15a increased plasma diabetic patients, correlating with severity. miR-15 plays an important insulin production pancreatic β-cells. By...
MicroRNA (miRNA) is a type of noncoding RNA that can repress the expression target genes through posttranscriptional regulation. In addition to numerous physiologic roles for miRNAs, they play an important role in pathophysiologic processes affecting cardiovascular health. Previously, we reported nuclear encoded microRNA (miR-181c) present heart mitochondria, and importantly, its overexpression affects mitochondrial function by regulating gene expression.To investigate further how miR-181...
Endothelial dysfunction and arterial stiffening play major roles in cardiovascular diseases. The critical role for the miR-181 family vascular inflammation has been documented. Here we tested whether can influence pathogenesis of hypertension stiffening.qPCR data showed a significant decrease miR-181b expression aorta older mice. Eight miR-181a1/b1-/- mice wild types (C57BL6J:WT) were followed weekly pulse wave velocity (PWV) blood pressure measurements. After 20 weeks, endothelial function...
Rationale: The mTORC1 (mechanistic target of rapamycin complex-1) controls metabolism and protein homeostasis is activated following ischemia reperfusion (IR) injury by ischemic preconditioning (IPC). However, studies vary as to whether this activation beneficial or detrimental, its influence on after IR little reported. A limitation prior investigations their use broad gain/loss function, mostly applied before stress. This can be circumvented regulating one serine (S1365) TSC2 (tuberous...
Proteotoxicity from insufficient clearance of misfolded/damaged proteins underlies many diseases. Carboxyl terminus Hsc70-interacting protein (CHIP) is an important regulator proteostasis in cells, having E3-ligase and chaperone functions often directing damaged towards proteasome recycling. While enhancing CHIP functionality has broad therapeutic potential, prior efforts have all relied on genetic upregulation. Here we report that CHIP-mediated turnover markedly post-translationally...
Stimulated PKG1α (protein kinase G-1α) phosphorylates TSC2 (tuberous sclerosis complex 2) at serine 1365, potently suppressing mTORC1 (mechanistic [mammalian] target of rapamycin 1) activation by neurohormonal and hemodynamic stress. This reduces pathological hypertrophy dysfunction increases autophagy. oxidation cysteine-42 is also induced these stressors, which blunts its cardioprotective effects.
Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show that cyclic GMP-selective phosphodiesterase 9A inhibition (PDE9-I) in both male ovariectomized female mice suppresses preestablished severe diet-induced obesity/CMS or without superimposed mild cardiac pressure load. PDE9-I reduces total body, inguinal, hepatic, myocardial fat; stimulates mitochondrial activity brown white improves CMS,...
MTORC1 integrates signaling from the immune microenvironment to regulate T cell activation, differentiation, and function. TSC2 in tuberous sclerosis complex tightly regulates mTORC1 activation. CD8+ cells lacking have constitutively enhanced activity generate robust effector cells; however, sustained activation prevents generation of long-lived memory cells. Here we show that manipulating at Ser1365 potently regulated activated but not basal Unlike nonstimulated TSC2-KO cells, expressing a...
Tuberous sclerosis complex-2 (TSC2) negatively regulates mammalian target of rapamycin complex 1 (mTORC1), and its activity is reduced by protein kinase B (Akt) extracellular response (ERK1/2) phosphorylation to activate mTORC1. Serine 1364 (human) on TSC2 bidirectionally modifies mTORC1 activation pathological growth factors or hemodynamic stress but has no impact resting activity. We now show this modification biases ERK1/2 not Akt-dependent TSC2-mTORC1 activation. Endothelin-1–stimulated...
We recently identified a nuclear-encoded miRNA (miR-181c) in cardiomyocytes that can translocate into mitochondria to regulate mitochondrial gene mt-COX1 and influence obesity-induced cardiac dysfunction through the pathway. Because liver plays pivotal role during obesity, we hypothesized miR-181c might contribute pathophysiological complications associated with obesity. Therefore, used miR-181c/d-/- mice study of hepatocyte lipogenesis diet-induced The were fed high-fat (HF) diet for 26...
ABSTRACT Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show inhibiting cyclic-GMP selective phosphodiesterase-9A (PDE9-I) suppresses established diet-induced CMS in ovariectomized female male mice. PDE9-I reduces abdominal, hepatic, myocardial fat accumulation, stimulates mitochondrial activity brown white fat, improves CMS, without altering or food intake. PDE9 localizes mitochondria, its...
Abstract We recently identified a nuclear-encoded miRNA (miR-181c) in cardiomyocytes that can translocate into mitochondria to regulate mitochondrial gene (mt-COX1), and influence obesity-induced cardiac dysfunction through pathway. Liver plays pivotal role during obesity. Therefore, we hypothesized miR-181c an important pathophysiological complications associated with used miR-181c/d -/- mice study the lipogenesis hepatocytes diet-induced obesity (DIO). Indirect calorimetric measurements...
Summary The mammalian target of rapamycin complex 1 (mTORC1) is tightly controlled by tuberous sclerosis complex-2 (TSC2) that regulated phosphorylation from kinases responding to environmental cues. Protein kinase G specifically modifies serine-1365 (S1364, human), and its (or phosphomimetic SE mutant) potently blocks mTORC1 co-activation pathological stress, while a phospho-silenced (SA) mutation does the opposite. Neither alter basal activity. Here we show S1365 exerts biased control over...
Recent reports suggest that mi(cro)RNAs, non-coding RNAs, can regulate numerous human genes. miRNAs play an important role in physiologic and pathologic processes of cardiovascular health. We identified a nuclear encoded miRNA (miR-181c) translocates into mitochondria to mitochondrial gene, ultimately affects function. To investigate how miR-181c leads cardiac injury, we designed miR-181-sponges, RNA molecules with ten repeated complimentary miR-181 “seed” sequences, generated set...
Rationale: Protein kinase G 1α (PKG1α) confers anti-hypertrophic effects in hearts subjected to mechanical and neurohumoral stress. Human heart failure with a reduced ejection fraction (HFrEF) mouse pressure overloaded present increased mechanistic target of rapamycin complex 1 (mTORC1) activity, protein aggregation, oxidative stress, and, as we previously described, PKG1α disulfide dimer formation indicative oxidation. Recently demonstrated that stimulation phosphorylates tuberin (TSC2) at...
Rationale: The Mechanistic Target of Rapamycin complex 1 (mTORC1) integrates signaling and sensory inputs to maintain cardiomyocyte homeostasis, itself is negatively regulated by the nexus tuberin (TSC2). We identified a novel TSC2 phosphorylation site S1365 (pS1365) targeted protein kinase G (PKG), which suppressed hormonal growth factor (PE or ET1)-stimulated mTORC1 activity attenuate pathological hypertrophy. This was recapitulated during stimulation with expression phospho-null (S1365A)...